The transforming growth factor-beta (TGF-.beta.) superfamily of cytokines regulate a diverse array of physiologic functions including cell proliferation and growth, cell migration, differentiation, development and apoptosis. This large family includes the TGF-.beta.s, activins, and bone-morphogenic proteins (BMPs) and each subgroup initiates a unique signaling cascade activated by ligand-induced serine/threonine kinase receptor complex formation (Wrana, Miner. Electrolyte Metab., 1998, 24, 120-130). These complexes, once formed, recruit and phosphorylate members of a family of cytosolic proteins, known as SMADs. SMADs exist as monomers in unstimulated cells but homo- or heterodimerize and translocate to the nucleus activating target gene transcription upon ligand binding. SMADs, therefore, connect the pathway of TGF-.beta. signaling from the cell membrane to the nucleus.
To date, nine vertebrate SMADs have been identified and these have been divided into subgroups based on their functional role in various pathways. SMAD1, 5, and MADH6, which is 80% homologous to SMAD1, all mediate signal transduction from BMPs while SMAD2 and 3 mediate signal transduction from TGF-.beta.s and activins. Collectively, these SMADs are known as the pathway-restricted SMADs and can form homo or heterodimers. SMAD4 has been shown to be a shared hetero-oligomerization partner to the pathway-restricted SMADs and is known as the common mediator. The last two members of the family, SMAD6 and 7, act to inhibit the SMAD signaling cascades often by forming unproductive dimers with other SMADs and are therefore classified as antagonistic SMADs (Heldin et al., Nature, 1997, 390, 465-471; Kretzschmar and Massague, Curr. Opin. Genet. Dev., 1998, 8, 103-111).
MADH6 (also known as MADH9 and SMAD9) is a putative member of a subgroup of SMAD family transcription factors which are regulated by bone morphogenic proteins (BMPs).
The MADH6 gene was first isolated from a human fetal brain cDNA library and shown to encode two alternatively transcribed mRNAs, termed MADH6a and MADH6b. This gene was found to reside on chromosome 13q12-q14 between BRCA2 and RB, a region that displays allelic losses in breast, liver and prostate cancers. It is therefore believed that MADH6 may be involved in growth inhibition and tumor suppression (Watanabe et al., Genomics, 1997, 42, 446-451). Northern blot analysis showed that expression of MADH6 isoforms was found in adult and fetal tissue to the same extent, with the strongest expression in the brain, lung and kidney.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of MADH6. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting MADH6 function. Therefore, antisense oligonucleotides may provide a promising new pharmaceutical tool for the effective and specific modulation of MADH6 expression.